Impaired mitochondrial function resulting in the production of reactive oxygen species and oxidative stress plays a key role in the aetiology of Alzheimer's disease (AD). Oxidative stress is accompanied by microglial activation and an increase in the release of nitric oxide (NO) and pro-inflammatory cytokines, which further compromises mitochondrial activity. These pathological changes may also contribute to neurodegeneration in other disorders, like Parkinson's disease, ischemic stroke and amyotropic lateral sclerosis. They are also seen in Mild Cognitive Impairment (MCI) a prodromal form of AD to which it progresses in a significant proportion of subjects.
The drugs most frequently employed for the treatment of AD are acetylcholine-esterase (AChE) inhibitors. Of these, donepezil has been shown to reduce the cytotoxic effects of oxidative stress and the release of NO and cytokines from activated microglia, but both of these actions occur at concentrations 10-100-fold higher than those inhibiting AChE. The occurrence of a potential protective effect against neurodegenerative processes at much higher than relevant therapeutic doses may explain why chronic treatment with donepezil of patients with MCI did not reduce the proportion converting to AD.
Oxidative stress and the release of pro-inflammatory cytokines also occurs in pathological conditions, such inflammatory bowel diseases (IBDs) ulcerative colitis and Crohn's disease, rheumatoid arthritis, type II diabetes and cardiac failure. The IBDs are characterized by strong leukocyte activation and infiltration into the intestinal tissues, the release of pro-inflammatory cytokines and enzymes and the formation of reactive oxygen species. The mucosa in patients with ulcerative colitis appears to be dominated by CD4+ lymphocytes with an atypical type 2 helper T cell (Th2) phenotype. Recruitment of inflammatory cells from the circulation is an important process to augment the inflammatory response. Activated macrophages produce pro-inflammatory cytokines TNF-α, IL-6 and IL-8 among others. TNF-α and IL-6 induce the expression of adhesion molecules like selectin, intercellular adhesion molecule-1 (ICAM-1) and adhesion molecule-1 in the vascular endothelium. This phenomenon causes the invasion of inflammatory cells into the mucosal layer. Leukocytes produce the superoxide radical and pro-inflammatory substances. These include arachidonic acid metabolites (leukotriene B4, prostaglandin E2), and nitric oxide (NO). NO interacts with superoxide radicals to produce peroxynitrite, which exerts a cytotoxic effect on gastrointestinal mucosa. Reactive oxygen metabolites play an important role in the direct injury of the intestinal mucosa. Therefore, in order to prevent this sequence of events and the resulting intestinal damage it is very important to reduce the release of pro-inflammatory cytokines and the perpetrators of oxidative-nitrative stress.
Current anti-inflammatory treatment for colitis employs 5-amino salicylate or its precursors, corticosteroids such as beclometasone or budesonide, immunosuppressive agents like azathioprine and immuno-regulatory agents like infliximab and adalimumab. However, while effective, some of the treatments may increase the risk of infections and produce other serious adverse effects in a significant proportion of patients.
Chyan et al., (J. Biol. Chem. 1999; 274: 21937-21942) reported that 3-indole-propionic acid (IPA) protects primary neurones in culture against oxidative damage induced by beta amyloid.